Familial inflammatory dilated cardiomyopathy

BACKGROUND: Systematic family screening has recently identified dilated cardiomyopathy as an inherited disorder in up to 30% of cases. Mutations in genes encoding proteins responsible for myocardial architecture have been identified, but additional pathophysiological mechanisms including inflammatory reactions have been proposed. AIMS: Identification and characterization of familial DCM, where at least one affected family member fulfils the criteria for inflammatory DCM may lead to a better understanding of the aetiology and pathogenesis of (inflammatory) DCM. METHODS AND RESULTS: Ten families were examined. In six families, clinical characteristics and mode of inheritance were compatible with pure fDCM, fDCM with conduction defect and autosomal recessive fDCM. In four families, (auto-)immune features were diagnosed in affected and non-affected family members. CONCLUSIONS: Familial DCM with an inflammatory component was identified as a specific subgroup of familial DCM. In most cases, the inflammatory process seems to modify, i.e. aggravate, the "classic, cytoskeletopathic" familial DCM, but in some, especially when taking clinical and genetic aspects into account, inflammatory (auto-)immune features can be addressed as the leading pathogenetic principle. Further elucidation of these families may provide a better insight into pathophysiologic processes and may aid in the development of specific therapeutic strategies.     

扩张型心肌病280例临床分析

目的:探讨近年来扩张型心肌病(DCM)的临床表现特点及预后。方法:对1998年1月~2004年6月收治的280例DCM患者的临床资料,以及其中187例(66·8%)的随访结果进行分析。结果:男221例(78·9%),女59例(21·1%),起病年龄为(48·0±14·2)岁;确诊时心功能NYHAⅠ~Ⅱ级者60例(21·4%),Ⅲ级者155例(55·4%),Ⅳ级者65例(23·2%);全部患者中8例(2·9%)为家族性DCM,起病年龄(35·4±11·4岁)明显小于散发患者(48·4±14·1)岁,P<0·01。253例(90·4%)患者出现各种心律失常,包括心房颤动71例(25·4%),多源室性期前收缩、短阵室性心动过速分别为90例(32·1%)、130例(46·4%),左束支传导阻滞64例(22·9%)。超声心动图显示,患者以左心房、左心室同时扩大(55·4%)或全心扩大(30·0%)为主;Ⅲ~Ⅳ级患者与Ⅰ~Ⅱ级者相比,左室舒张末期内径[(68·9±8·4)∶(63·8±7·8)mm]明显增大,左室射血分数[(31·8±10·1)%∶(41·8±12·0)%]显著降低,均P<0·01。药物治疗中,血管紧张素转化酶抑制剂和β-受体阻滞剂使用率分别为70·1%(199例)、60·0%(168例)。187例(66·8%)患者获得随访,随访时间(29·8±23·2)个月;随访中死亡50例,其中心力衰竭死亡27例(54·0%),猝死20例(40·0%);另有7例患者接受心脏移植治疗。在未行心脏移植情况下,患者确诊后1、2、5年生存率分别为93·4%、86·0%、65·3%,高于国内以往报道。8例家族性DCM患者5年生存率(40·0%)低于散发患者(68·5%),P<0·05。结论:DCM患者确诊时心功能多已达Ⅲ~Ⅳ级,伴有各种心律失常及心腔扩大;2年和5年生存率较以往已有改善,心力衰竭和猝死仍是主要死亡原因;2·9%的患者为家族性DCM,起病年龄较轻,预后较差。     

Evidence-based diagnosis of familial non-X-linked dilated cardiomyopathy. Prevalence, inheritance and characteristics.

AIMS: To assess the prevalence of familial non-X-linked dilated cardiomyopathy, to diagnose early asymptomatic cases evaluate inheritance and characterize clinical phenotypes. METHODS AND RESULTS: We screened 472 relatives of 104 consecutive patients diagnosed with dilated cardiomyopathy; males with X-linked dilated cardiomyopathy were excluded based on systematic immunohistochemical and molecular analysis. Relatives underwent clinical examination, electrocardiography, echocardiography and serum creatine-phosphokinase determination. Twenty-six index patients (25%) had familial disease: four youths (< or = 20 years) had rapidly progressive outcome and underwent emergency transplantation. In a sib-pair, the onset was with atrioventricular block. Inheritance was autosomal dominant in 15, undetermined in seven (four sib-pairs); mitochondrial DNA pathological mutations were found in four. The screening identified 23 newly diagnosed relatives in the familial group. Transplantation (P = 0.04) and atrial fibrillation (P = 0.04) were more frequent, and left bundle branch block (P = 0.04) less frequent in index patients with familial than in those with non-familial disease. Several non-affected relatives had instrumental abnormalities potentially useful as pre-clinical markers: their prevalence was similar in both groups. CONCLUSIONS: The prevalence of familial, non X-linked dilated cardiomyopathy was 25%. The immediate benefits of screening family members of index patients was early diagnosis in unaware symptomless affected relatives.     

Echocardiography of dilated cardiomyopathy in children

Echocardiography is useful and reliable in the diagnosis and management of children with dilated cardiomyopathy. M-mode echocardiography provides quantitative information of left ventricular and left atrial dimensions and left ventricular wall thickness. Left ventricular function including shortening fraction, mean velocity of circumferential fiber shortening (V cf), systolic time intervals, left ventricular wall thickening and thinning rate, isovolumic contraction time, and wall stress can be derived from M-mode study. Left ventricular and left atrial dimensions are usually 1.5 times normal. Left ventricular systolic function is markedly reduced. Shortening fraction can be easily obtained and is the most informative index for assessing the severity of illness. Very low shortening fraction at presentation and follow-up (12-15%) is a poor prognostic sign. Two-dimensional echocardiography is valuable for excluding valvular lesion or coronary artery anomaly and detection of intracardiac thrombus. The left ventricular free wall is usually more severely affected than the ventricular septum as seen by two-dimensional echocardiography.     

Electrocardiographic features differentiating dilated cardiomyopathy from hypertrophic cardiomyopathy

To determine the usefulness of electrocardiographic (ECG) features in differentiating between hypertrophic cardiomyopathy with features mimicking dilated cardiomyopathy (D-HCM) and true dilated cardiomyopathy (DCM), we compared ECGs of 52 consecutive patients (11 with D-HCM, 41 with DCM). Left atrial dimension, left ventricular internal dimension, and septal and posterior wall thickness were employed as echocardiographic indexes, while QRS duration, amplitude of RV₅ or V₆ + SV₁, number of abnormal Q waves, P-terminal force in V₁, and frontal plane QRS axis were used as ECG parameters. The patients with D-HCM demonstrated a larger number of abnormal Q waves (P < .0001), greater prolongation of QRS duration (P < .0001), and lower amplitude of RV₅ or V₆ + SV₁ (P < .0001). In all cases of D-HCM, atrial overload was observed and abnormal QRS axis in 9 (82%) of the 11 patients. These features were noted in 21 (51%) and 17 (41%), respectively, of the 41 DCM patients (P < .005 and P < .05, respectively). Despite significant differences in the echocardiographic parameters between D-HCM and DCM, excluding left ventricular end-diastolic dimension, ECG abnormalities were more significant between the two groups. The results indicate that ECG features are extremely useful in differentiation between DCM and D-HCM.     

Prognostic value of serial cardiac assessment and familial screening in patients with dilated cardiomyopathy

OBJECTIVES: This prospective study was performed to analyse whether routine clinical follow-up investigations at 12+/-6 months add to risk stratification and improve survival rates in patients with a first diagnosis of dilated cardiomyopathy (DCM). METHODS: Four hundred and eighty consecutive patients (mean age 53.4+/-12.3 years, 369 males, mean NYHA class 2.4+/-0.8) with invasively confirmed DCM were included and followed for 3.9+/-3.5 years. Patients were requested to adhere to a follow up investigation within 6-18 months either at the referring physicians or at our out patient department. Two hundred and eighty-one of the 480 patients presented for follow up which consisted of a detailed evaluation of symptoms, standardized physical examination, 12-lead-electrocardiogram recording and echocardiography. Seventeen patients were lost for follow up, 182 did not seek specialized medical follow up. Patients outcome was assessed by structured telephone interviews. RESULTS: Independent predictors of death or transplantation at initial diagnosis were LV-ejection fraction <30% (P=0.0001, risk ratio 2.25), LV-end diastolic pressure >or=15 mmHg (P=0.002, risk ratio 2.0), age >or=54 years, (P=0.04, risk ratio 1.55), and presence of left bundle branch block (P=0.046, risk ratio 1.53). On follow up investigations only deterioration of clinical status by at least one NYHA-class (P=0.001, risk ratio 2.6) and new onset or worsening of mitral regurgitation (P=0.02, risk ratio 1.8), remained independent prognostic factors for cardiac death. Patients who presented for routine follow up revealed significant better 5-year survival rates (n=281, 70%) than those who did not (n=153, 55%, P=0.005). CONCLUSIONS: Routine clinical follow up investigations within 6-18 months after first diagnosis of DCM adds to risk stratification and improves survival rates.     

Circulating cardiac autoantibodies in dilated cardiomyopathy and myocarditis: pathogenetic and clinical significance

Dilated cardiomyopathy (DCM) is a relevant cause of heart failure and a common indication for heart transplantation. It may be idiopathic, familial/genetic, viral, autoimmune or immune-mediated associated with a viral infection. Myocarditis is an inflammatory disease of the myocardium; it may be idiopathic, infectious or autoimmune and may heal or lead to DCM. Thus, in a patient subset, myocarditis and DCM are thought to represent the acute and chronic stages of an organ-specific autoimmune disease of the myocardium. In keeping with this hypothesis, autoimmune features in patients with myocarditis/DCM include: familial aggregation; a weak association with HLA-DR4; abnormal expression of HLA class II on cardiac endothelium on endomyocardial biopsy; and detection of organ- and disease-specific cardiac autoantibodies of the IgG class in the sera of affected patients and symptom-free relatives. The cardiac autoantibodies detected by immunofluorescence are directed against multiple antigens. Two of these, first identified using immunoblotting and confirmed by ELISA, are the atrial-specific alpha- and the ventricular and skeletal muscle beta-heavy chain isoform. The alpha-myosin isoform fulfils the expected criteria for organ-specific autoimmunity, in that immunization with cardiac, but not skeletal myosin reproduces, in susceptible mouse strains, the human disease phenotype of myocarditis/DCM; in addition, alpha-myosin is entirely cardiac-specific. Additional antigenic targets of heart-reactive autoantibodies include unknown sarcolemmal proteins, mitochondrial enzymes, beta-adrenergic and muscarinic receptors. For some of these antibodies, there is in vitro evidence for a functional role. The organ-specific cardiac autoantibodies detected by immunofluorescence in symptom-free relatives were associated with echocardiographic features suggestive of early disease. Mid-term follow-up suggests that these antibodies are predictive markers of progression to DCM among symptom-free relatives with or without abnormal echocardiographic findings.     

Cardiac troponin T Arg92Trp mutation and progression from hypertrophic to dilated cardiomyopathy

BACKGROUND: Mutations in the cardiac troponin T gene causing familial hypertrophic cardiomyopathy (HCM) are associated with a very poor prognosis but only mild hypertrophy. To date, the serial morphologic changes in patients with HCM linked to cardiac troponin T gene mutations have not been reported. HYPOTHESIS: The aim of this study was to determine the long-term course of patients with familial HCM caused by the cardiac troponin T gene mutation, Arg92Trp. METHODS: In all, 140 probands with familial HCM were screened for mutations in the cardiac troponin T gene. RESULTS: The Arg92Trp missense mutation was present in 10 individuals from two unrelated pedigrees. They exhibited different cardiac morphologies: three had dilated cardiomyopathy-like features, five had asymmetric septal hypertrophy with normal left ventricular systolic function, one had electrocardiographic abnormalities without hypertrophy, and one had the disease-causing mutation but did not fulfill the clinical criteria for the disease. The mean maximum wall thickness was 14.1 +/- 6.0 mm. The three patients with dilated cardiomyopathy-like features had progressive left ventricular dilation. Three individuals underwent right ventricular endomyocardial biopsy. There was a modest degree of myocardial hypertrophy (myocyte diameter: 18.9 +/- 5.2 microm), and minimal myocardial disarray and mild fibrosis were noted. CONCLUSION: The Arg92Trp substitution in the cardiac troponin T gene shows a high degree of penetrance, moderate hypertrophy, and early progression to dilated cardiomyopathy in Japanese patients. Early identification of individuals with this mutation may provide the opportunity to evaluate the efficacy of early therapeutic interventions.     

Reversal of dilated to hypertrophic cardiomyopathy after alcohol abstinence

Left ventricular dilatation and systolic dysfunction develop in 14-16% of patients with hypertrophic cardiomyopathy. Such findings may easily be misdiagnosed as dilated cardiomyopathy. It is unknown whether left ventricular dilatation and systolic dysfunction in patients with hypertrophic cardiomyopathy are reversible. A 35-year-old man had been a heavy drinker for 13 years and was abstinent for 1 year. Five years previously he suffered cardiac arrest and, based on echocardiographic, radionuclide, and cardiac catheterization findings, the diagnosis of alcohol-induced dilated cardiomyopathy was established. At presentation the heart was of normal size, with concentric left ventricular hypertrophy and only slightly reduced systolic function. Hypertrophic cardiomyopathy was diagnosed since no other cause for left ventricular hypertrophy could be detected. In hypertrophic cardiomyopathy, alcohol may induce reversible systolic dysfunction and left ventricular dilatation.     

ECG characteristics of dilated cardiomyopathy

To elucidate the electrocardiographic (ECG) characteristics of dilated cardiomyopathy (DCM), the authors analyzed the 12-lead ECGs and echocardiograms in 45 patients with DCM, 54 patients with left ventricular (LV) dilatation secondary to valvular heart disease (VHD), 101 hypertensive patients with LV hypertrophy, and 63 normal control subjects. In addition, serial ECG and echocardiographic changes in DCM during a mean follow-up period of 1.6 years were evaluated. Sokolow's criterion (S wave in lead V₁ [SV₁] + R wave in lead V₅ or V₆ [RV₅ or RV₆] > 35 mm) was met comparably in patients with DCM (69%), VHD (61%), and hypertension (74%) (P = NS). Notably, RV₆ in DCM was the highest among the four groups and correlated with the degree of LV dilatation. In contrast, the R waves in leads I, II, and III (RI, RII, RIII) in DCM were the lowest and were not affected by the degree of LV dilatation, although RII and RIII in VHD and RI in hypertension correlated with the degree of LV dilatation and hypertrophy, respectively. As a result, all voltage ratios of RV6/RI, RII, RIII in DCM were not only the highest, but also increased linearly as the LV dilated progressively during the follow-up period. In particular, RV₆ over the maximum R wave in leads I, II, and III (RV₆/Rmax) in DCM correlated with the degree of LV dilatation and inversely correlated with ejection fraction. Subjects with DCM had a significantly higher RV₆/Rmax than did patients with VHD, hypertension, and normal subjects (3.4 vs 1.7, 1.4, 1.2, respectively; P < .001), and this ratio of ≥3 was seen in 67% of the DCM patients versus 4% of the VHD patients, 1% of the hypertensive patients, and 0% of the normal subjects. Thus, DCM commonly shows the ECG signs of LV hypertrophy, but characteristically has the high voltage ratios of RV6/RI, RII, RIII.     

Haemochromatosis gene mutations in idiopathic dilated cardiomyopathy

BACKGROUND—Two common mutations of the haemochromatosis associated gene (HFE) (cys282tyr (C282Y) and his63asp (H63D)) have been implicated in haemochromatosis and as modulators in cardiovascular disease.
OBJECTIVE—To investigate the role of these mutations in the pathogenesis of idiopathic dilated cardiomyopathy.
DESIGN AND SETTING—Case-control and prospective cohort study of patients attending a cardiomyopathy unit in a tertiary referral cardiac centre.
METHODS—207 unrelated white patients with dilated cardiomyopathy, followed up for 259 patient years, and 200 controls were tested for HFE C282Y and H63D mutations by polymerase chain reaction and restriction digestion.
RESULTS—31/207 patients (15%) v 24/200 controls (12%) carried C282Y (adjusted odds ratio (OR) 1.2 (95% confidence interval 0.7 to 2.2)), 74/207 (36%) v 53/200 (27%) carried H63D (OR 1.6 (1.1 to 2.5)), and 10/207 (4.8%) v 4/200 (2%) were compound heterozygotes (OR 2.6 (0.8 to 8.5)). Four patients and six controls were H63D homozygous and one was C282Y homozygous. There was a progressive increase in mean serum iron ([Fe]) and transferrin saturations from patients with no mutation ([Fe] = 16.3 µmol/l, transferrin saturation = 23.7%) through H63D heterozygotes (17.5 µmol/l, 25.8%), C282Y heterozygotes (17.1 µmol/l, 26.6%), H63D homozygotes (20.0 µmol/l, 33.5%), compound heterozygotes (26.8 µmol/l, 41.7%), and C282Y homozygotes (34 µmol/l, 71%). At follow up (median 90 months) the rate of death or cardiac transplantation was 52/207 (25%). C282Y heterozygotes had less ventricular dilatation (mean (SD): 59.9 (1.7) mm v 64.9 (0.9) mm, p < 0.05), better fractional shortening (24 (1.7)% v 18.8 (1.4)%, p < 0.01), and a trend towards improved survival without transplantation. [Fe] and transferrin saturation did not correlate with disease severity and were not associated with reduced survival.
CONCLUSIONS—The frequency of the H63D mutation is significantly increased in patients with idiopathic dilated cardiomyopathy. As H63D has a relatively minor effect on iron status, the mechanism of this association may be unrelated to iron metabolism.


Keywords: dilated cardiomyopathy; genetics; haemochromatosis     

Prognosis of idiopathic dilated cardiomyopathy

Previous reports in referral populations have emphasized the poor prognosis of dilated cardiomyopathy. This study evaluated mortality and morbidity in patients presenting at a referral center between 1989 and 1993. One hundred seventy-two consecutive patients were studied. At presentation, 82 were in New York Heart Association functional class III/IV. Mean (+/- SD) left ventricular end-diastolic dimension was 69 +/- 11 mm, ejection fraction was 25 +/- 10%, VO2 max was 21 +/- 9 mL/min/kg, and sodium was 136 +/- 9 mM. Treatments included vasodilators (n = 157, 92%), anticoagulation (n = 50, 29%), amiodarone (n = 52, 30%), and cardiac defibrillator (n = 5, 3%). During the follow-up period (mean, 26 +/- 29 months), 16 patients died and 60 developed progressive heart failure; 46 (27%) required cardiac transplantation. The majority of the patients (102, 59%) were stable or improved. Established prognostic determinants (left ventricular end-diastolic dimension, ejection fraction, sodium, and arrhythmia) were of low predictive value for the development of progressive heart failure or sudden death. The 1- and 2-year probabilities of death or transplantation was 16 and 21%, respectively (death only 6 and 7%, respectively). These observations are subject to referral bias, but suggest that the majority of patients can remain stable. Any improvement in survival compared to earlier experience can be due to earlier diagnosis, availability of transplantation, and new heart failure management strategies.     

Comparison of noninvasive measures of contractility in dilated cardiomyopathy

Left ventricular performance is usually quantified by ejection phase indices such as ejection fraction, cardiac output, and fractional shortening. The load-dependence of these measures may result in inaccurate estimation of intrinsic myocardial contractility in states of chronic pressure or volume overload. End-systolic and stress-shortening relations have been proposed as measures of contractile state insofar as they are theoretically independent of preload and incorporate afterload. This article examines the behavior of these relations in response to changes in loading conditions and contractile state and reviews their application utilizing noninvasive methodology, particularly in the setting of dilated cardiomyopathy.     

扩张型心肌病患者发生电风暴的危险因素

目的 了解扩张型心肌病(扩心病)患者电风暴的发生率,并探讨其发生电风暴的相关危险因素.方法 观察53例住院的扩心病患者,通过心电监护或24h动态心电图识别电风暴,根据是否发生电风暴进行分组,采用单因素和多因素分析,发现危险因素.结果 34％患者在住院期间发生电风暴,房颤病史(OR:2.2,95％CI:1.2-5.0; ...     

阻塞性睡眠呼吸暂停综合征与扩张型心肌病

随着对阻塞睡眠呼吸暂停综合征(OSAS)认识的深入,OSAS与各类心血管疾病的相关性也逐渐得到重视。2009年中华医学会呼吸病学分会睡眠学组会同心血管病学会参照国外有关研究发表了《睡眠呼吸暂停与心血管疾病专家共识》,成为进一步促进、密切两个学科之间研究的新起点。文章对如何早期认识、诊断OSAS合并扩张型心肌病(DCM)做一简要介绍,强调DCM患者合并OSAS诊断的临床意义,分析CPAP治疗对DCM患者恢复心脏功能及心脏结构的临床价值。     

Structure and function of contractile proteins in human dilated cardiomyopathy

The pathogenesis of reduced systolic left ventricular function in dilated cardiomyopathy is yet unclear. To analyze a possible involvement of contractile protein, function and structure of left ventricular myofibrils were examined in hearts of patients with advanced cardiomyopathy undergoing heart transplantation and in normal control hearts (from renal transplant donors). Myosin and actin content of the left ventricular myocardium was slightly reduced in cardiomyopathic hearts. Myofibrillar polypeptide composition was determined using two-dimensional electrophoresis and immunoblotting. No differences in constituting polypeptides were apparent, including Z-line proteins and proteins of the endosarcomeric lattice. M-line-bound creatine kinase was identical in both groups. Further, basal and maximal myofibrillar adenosine triphosphatase (ATPase) activities were unaltered in dilated cardiomyopathy. The structure of purified myosin was identical in both groups by the following criteria: electrophoretic mobility of native myosin, identical pattern of light chains after isoelectric focusing, identical cleavage peptides of myosin's heavy chain, and identical patterns after immunoblotting of heavy chain cleavage peptides using polyclonal antibodies generated against myosin from normal and cardiomyopathic ventricles. Ca2+-activated, K+-EDTA-activated and actin-activated myosin ATPase activities were identical in control and cardiomyopathic hearts. A structural alteration or functional defect of myofibrils does not seem to be primarily involved in the pathogenesis of reduced myocardial contractility in dilated cardiomyopathy.     

A rare cause of reversible dilated cardiomyopathy: hypocalcemia

Hypocalcemia is a rare cause of reversible heart failure. We reported a 40-year-old woman who had severe heart failure resistant to the usual antifailure therapy. She had severe hypocalcemia due to hypoparathyroidism after strumectomy. Echocardiography showed a large left ventricle with very low ejection fraction of 25% and moderate mitral regurgitation. After supplementation of calcium and vitamin D, her clinical situation and hemodynamics improved rapidly. At 15 months, myocardial impairment resolved fully. In conclusion, hypocalcemia should be considered in the differential diagnosis of resistant severe heart failure.     

扩张型心肌病患者窦性心率震荡的研究

目的 探讨扩张型心肌病患者窦性心律震荡（HRT）的特征及其对预后的影响。方法 选择扩张型心肌病并室早的患者187例，选择同期有室早而无器质性心脏病100例作对照组，分别检测窦性心率震荡的初始（TO）和窦性心率震荡的斜率（TS）：将窦性心率震荡分类为HRT1（TO〈0且TS〉2．5ms／RR间期）、HRT2（TO≥0或TS≤2．5ms／RR间期）、HRT3（TO≥0且TS≤2．5ms／RR间期），分别对不同心功能分级，存活组及死亡组进行分析。结果 扩张型心肌病与对照组比较TO、TS均有显著性差异（P〈0．001和P〈0．005）。在心功能Ⅲ级与Ⅳ级时HRT2,在两组间无显著性差异（p〉0．05），其他不同分级心功能的窦性心率震荡分类均有显著差异（p〈0．05或p〈0．01）。存活组与死亡组比较窦性心率震荡分类亦有显著性差异（HRT1p〈0．01，HRT2p〈0．05，HRT3p〈0．01）。结论 扩张型心肌病患者存在室早后窦性心率震荡减弱或消失现象，窦性心率震荡对其预后有一定的预测价值。     

扩张型心肌病12导联动态心电图分析

目的观察扩张型心肌病的24h12导联动态心电图改变。方法60例经心脏超声检查诊断为扩张型心肌病的病例入选，并行24h12导联动态心电图监测。结果所有病例动态心电图均有异常改变，其中以室性早搏为最常见（97％），其次是ST-T改变（60％）和室性心动过速（50％）。心功能越差，复合心律失常越多见。结论扩张型心肌病的心律失常发生率高且多样，有复合心律失常的患者有必要进行心脏超声心动图检查。